This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Clinical sequelae of HCV infection now comprise the leading indication for liver transplantation in the United States and account for significant morbidity and mortality each year. Despite potentially grave clinical consequences, the only licensed therapy for chronic hepatitis C infection is alpha interferon, either alone or in combination with the nucleoside analog ribavirin. Our work hypothesized that the reciprocal and cognate interaction between CD4+ T cells and antigen presenting cells is insufficient early in HCV infection and that the failure to generate a protective neutralizing anti-HCV response during the acute stages of infection is an immediate result of this inadequacy. We analyzed the peripheral and intrahepatic memory cellular immune response in experimental chimpanzees that are chronically infected or have acutely resolved HCV infection as well as in human patients infected with HCV. We found that T cell escape mutations observed in vivo over the course of 7 years of chronic infection affect viral fitness and that those mutations that stabilized in the viral population provided a balance between adequate replication and virion production as well as escape from the T cell response.